Efficacy of β-Blockers in Decreasing Mortality in Sepsis and Septic Shock Patients: A Systematic Review

Sepsis is a life-threatening condition leading to various organ dysfunction due to an underlying infection. Despite providing appropriate treatment, it is still one of the most common causes of death among patients who are admitted to the intensive care unit (ICU). So, multiple studies have been conducted to identify the potential benefits of various drugs in decreasing mortality in sepsis apart from its traditional treatment options. This study aims to identify whether β-blockers play a role in decreasing mortality in sepsis and septic shock patients because of their potential benefits on several organ systems. Medical databases such as Google Scholar, Summon, PubMed Medical Subject Headings (MeSH), PubMed, Science Direct, Cochrane Library, and Multidisciplinary Digital Publishing Institute (MDPI) were systematically searched for relevant publications. The identified articles were assessed based on the inclusion and exclusion criteria, and 11 research articles were finalized, for which quality appraisal was done using appropriate appraisal tools. β-blockers significantly lowered the in-hospital mortality in sepsis and septic shock patients, and they were also associated with better patient outcomes. As there are limited studies, further research needs to be done to explore the role of β-blockers in decreasing mortality in critically ill populations such as sepsis and septic shock patients.


Introduction And Background
In the landscape of critical care, septic shock remains a challenge that needs to be overcome.Among patients who are admitted to the intensive care unit (ICU), sepsis or septic shock remains the main cause of death.Progression from sepsis to septic shock is characterized by dysfunction of more than two organ systems along with refractory hypotension and increased lactate levels due to tissue hypoperfusion.The underlying pathophysiology consists of marked circulatory, immunologic, hematologic, and metabolic abnormalities, which is the reason for increased mortality [1].As a physiologic response to the underlying systemic infection and inflammation, there is a widespread activation of the sympathetic nervous system and a surge of catecholamine levels [2].However, this results in stimulation of β-adrenergic receptors in the heart.The consequence of this β-receptor stimulation is an increase in heart rate, contractility, and cardiac output to cope with the increasing metabolic demands, which can further cause increased stress on the heart and also an imbalance between oxygen supply and demand.
The interplay of these physiologic responses on the heart to the sepsis or septic shock can result in sepsisinduced cardiomyopathy (SIC) [3] and increased incidence of tachyarrhythmias such as sinus tachycardia, atrial fibrillation, and atrial flutter.Tachyarrhythmias are proposed to be an independent risk factor for death or poor prognosis in patients with severe sepsis and septic shock [2][3][4].They can further increase the stress on the heart by impairing ventricular filling and increasing myocardial oxygen consumption [3], which in turn can lead to ischemia of the heart.Prolonged catecholamine exposure and excessive activation of the β-receptors are also primary factors linked to heart failure in sepsis [5].
Traditionally, the treatment for septic shock focuses on source control, antibiotic therapy, fluid resuscitation, and vasoactive agents such as norepinephrine (NE) to maintain the mean arterial pressure (MAP) above 65 mmHg.In cases of refractory shock, vasopressin should be combined with NE to reach an acceptable level of pressure control and maintain tissue perfusion.Other supportive measures, such as mechanical ventilation and renal replacement therapy, are also used [4].Patients with sepsis who continue to have tachycardia even after adequate fluid resuscitation carry a poor prognosis [4].Therefore, controlling the heart rate might improve the outcomes in the management of sepsis [4].
β-blockers, which are generally used for cardiovascular conditions such as tachycardia, arrhythmias, chronic heart failure, and myocardial infarction (MI) [2], work by reducing heart rate, which can increase the time for diastolic filling and improve the efficiency of the cardiovascular system by maintaining tissue perfusion.Lack of tissue perfusion and tachyarrhythmia, which is a known predictor of poor prognosis in septic shock [6], can exacerbate the ischemia of the heart by causing cardiac dysfunction due to decreased coronary perfusion and increased myocardial oxygen consumption.As β-blocker usage can decrease cardiovascular stress by decreasing heart rate, which can, in turn, protect the already ischemia-prone heart from a secondary MI [7].So, various studies have been done to identify the beneficial effects of β-blockers in the treatment of sepsis and septic shock patients.Even though β-blockers are proposed to be helpful in septic shock patients by decreasing mortality for all of the above reasons, they can also cause hypotension by decreasing cardiac output [1,2], which can lead to deleterious effects.So, we still need further studies to know which type of β-blocker to use, i.e., short-acting or long-acting, their dosage, how often to give these drugs, and for how long they should be given during the patient's ICU stay.
This study aims to summarize the evidence of the use of β-blockers in decreasing mortality in septic shock patients.

Review Methodology
PRISMA 2020 guidelines were used to conduct this systematic review [8].

Search Strategy and Sources Used
We searched PubMed, PubMed Medical Subject Headings (MeSH), Multidisciplinary Digital Publishing Institute (MDPI), Summon, Cochrane Library, Science Direct, and Google Scholar to identify the relevant articles.Table 1 shows the number of papers identified using each database.

Search strategy
Database used

Inclusion and Exclusion Criteria
We included articles published in the past 10 years written in English or if the full-text English translation was available.The patient age group included patients above 18 who were admitted to the ICU and satisfied the sepsis or septic shock criteria.For exclusion criteria, articles that were not published in English, patients who were less than 18 years old, and patients who were above 18 years old and admitted to the ICU but did not satisfy the sepsis or septic shock criteria.

Selection Process
The relevant articles were imported to Endnote and duplicate papers were removed.Each qualified article was screened by going through titles and abstracts.After shortlisting the remaining articles, they were assessed for availability of full text.The selected relevant articles with full text were searched for inclusion and exclusion criteria, and articles that did not satisfy these criteria were excluded.

Quality Appraisal of the Shortlisted Articles
The relevant quality appraisal tools were used for all the shortlisted articles based on the type of study conducted.Joanna Briggs Institute (JBI) [9] was used to assess the quality of observational studies, while the Assessment of Multiple Systematic Review (AMSTAR 2) [10] tool was used for systematic review.Narrative reviews were assessed with the Scale for the Assessment of Narrative Review (SANRA) [11], and for randomized controlled trials (RCT), the Cochrane risk-of-bias tool for randomized trials (RoB 2) [12] was used.Only articles that met the quality appraisal criteria were included in this systematic review.

Process of Collecting Data
After the articles were selected for the systematic review, the primary outcome assessed was the mortality benefits of β-blocker usage in sepsis and septic shock patients, along with other additional information such as their protective effects on various organ systems and their role in in-hospital outcomes.

Study Identification and Selection
A total of 566 relevant articles were identified using databases such as PubMed, PubMed (MeSH), MDPI, Summon, Cochrane Library, Science Direct, and Google Scholar.In total, 540 unique duplicate articles were removed before being reviewed in detail.Further search was done to find only articles that were in English.As a result, 140 additional articles were identified.After reviewing these articles in detail by going through the titles and abstracts, 33 articles were shortlisted.The articles that were shortlisted were assessed for eligibility and quality using relevant quality appraisal tools, and a total of 11 articles were finalized for indepth review.Figure 1 represents the Preferred Reporting Items for the Systemic Review and Meta-Analysis (PRISMA) flowchart, which shows the selection process of all these articles.The finalized articles were assessed using the relevant quality appraisal tools.Table 3 shows the quality appraisal results using SANRA.

SANRA Cruz et al. [6] Fuchs et al. [13]
Importance for the readership justified 2 2 Question formulation and aims stated 2 2 Search for literature described   Table 5 shows the quality appraisal results using the JBI tool.

JBI critical appraisal Yang et al. [2] Ge et al. [4]
Were the two groups similar and recruited from the same population?

Sepsis and Its Mortality Rate
Despite the advances in recognizing and treating the underlying infections in sepsis, it still has a high mortality rate of 20-30% [2].Among hospitalized patients, it is the leading cause of death with a 30-40% mortality rate [4].About 19.7% of global deaths are due to sepsis, which is approximately 49 million cases in 2017 [1].According to one study, severe septic shock carries a mortality rate of 50-60% in the critically ill population [16].Sepsis can progress to SIC in 50% of sepsis patients and up to 70% of septic shock patients, which is also one of the causes of the increased rate of mortality [3,14].

Pathophysiology of Sepsis and Its Effect on Various Organ Systems
Sepsis, which stems from an underlying infection, results in excessive vasodilation and exaggerated catecholamine surge.This endogenous catecholamine surge leads to excessive activation of the adrenergic system.This can cause an increase in heart rate, stroke volume, and mean arterial pressure.However, this excessive and continuous activation of the adrenergic system can cause tachyarrhythmias such as atrial fibrillation and atrial flutter that can impair diastolic filling and myocardial perfusion, which can further impair myocardial contractility, resulting in decreased left ventricular ejection fraction.This decrease in ejection fraction leads to oxygen supply and demand mismatch, worsening metabolic acidosis by increasing lactic acid levels.Developing tachyarrhythmias in the setting of sepsis can lead to SIC, which is defined as decreased left ventricular ejection fraction, left ventricular dilation, and complete recovery in 7-10 days [6].
According to a study, the echocardiography shows around 50% of individuals with septic shock develop cardiomyopathy [6].As all these deleterious effects are caused by continuous stimulation of the adrenergic system, various studies have been conducted to study the effectiveness of β-blockers in decreasing catecholamine release and decreasing sympathetic activity, which can, in turn, improve heart rate and diastolic function, which can be associated with better patient outcomes and mortality rate.

Mechanism of Action of β-Blockers
β-blockers are of two types, namely selective and non-selective.Selective β-blockers such as atenolol, acebutolol, bisoprolol, esmolol, and metoprolol are the ones that block β1-receptors that are found mainly in cardiac nodal tissue, cardiac myocytes, and also on kidneys [17].Whereas, non-selective β-blockers such as propranolol, nadolol, and sotalol block both β1 and β2-receptors.β2 receptors are found mainly in bronchial and smooth muscles [18].
Circulating catecholamines such as epinephrine and norepinephrine act on β1 and β2-receptors.Both of these are G-protein coupled receptors that work by conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (CAMP) via adenyl cyclase, which in turn leads to an increase in intracellular calcium ion (Ca 2+ ).This causes phosphorylation of myosin light chains to cause muscle contraction.Activation of β1-receptors in the heart leads to sinoatrial (SA) node, atrioventricular (AV) node, and ventricular muscle firing that leads to an increase in contractility (inotropy), heart rate (chronotropy), and cardiac conduction timing (dromotropy).Whereas, activation of β1-receptors in the kidneys causes secretion of renin and eventually leads to an increase in the blood volume [17].β-blockers work by competing with catecholamines such as epinephrine and norepinephrine for β-receptor sites.This blockade leads to a decrease in inotropy, chronotropy, and dromotropy and an increase in lusitropy (relaxation) of the heart [17].

Protective Effect of β-Blockers When Used in Septic Shock
Studies indicate that β-blockers have the potential to lower heart rate and reduce sympathetic activity [2,7].Berk et al. [19] was the one who first studied the use of β-blockers in 1969 to diminish the sympathetic nerve activation in sepsis, which can be associated with decreased mortality [2].They can also improve hemodynamics by enhancing stroke index, systemic vascular resistance, and left ventricular stroke work indices (Morelli et al. [20]).Additionally, they play a role in regulating the inflammatory response [2,3] by decreasing inflammatory mediators like interleukin-6 (IL-6), high mobility group box 1 protein (HMGB1), and tumor necrosis factor-alpha (TNF-α) [2] while also preventing cardiomyocyte death.They can also reduce markers of cardiac injury [1] and help preserve myocardial function [14].
Blocking the adrenergic receptor could potentially avoid catecholamine toxicity in cases of septic shock [16].
When β-blockers are paired with standard septic shock treatments, there may be an enhancement in cardiac function and vascular responsiveness to catecholamines, as suggested by Kimmoun et al. [3,21].Study shows that selective β-blocker esmolol increases oxygen supply while decreasing oxygen consumption and also reduces cardiac myocyte injury markers like troponin I (TnI) levels [14].All of which can eventually improve patient prognosis and lower mortality rates [3].

Analysis of Various Studies in Decreasing Mortality in Septic Shock by Using β-Blockers
A retrospective cohort study was conducted in patients with sepsis using Medical Information Mart for Intensive Care-IV (MIMIC-IV) and the emergency ICU databases to assess for in-hospital mortality.This study showed that in-hospital mortality was significantly lower in the β-blocker group compared to the nonβ-blocker group.The in-hospital mortality for the β-blockers was 9.9%, and the non-β-blocker group was 19.5% [2].
A propensity score matching (PSM) analysis showed that β-blockers were associated with improved 28 and 90-day mortality, especially when long-acting β-blockers were used, whereas short-acting β-blockers did not [4].
A randomized controlled trial that included 100 SIC patients with a heart rate above 100/min showed that the use of esmolol in these patients achieved a target heart rate of 80-100 bpm without decreasing myocardial contractility and worsening adverse events, along with lowering their 28 and 90-day mortality [3].
Similarly, another study showed that inhibition of catecholamine secretion by β-blockers brings down the heart rate to < 95bpm within 24 hours, which can have a positive impact on the patient outcome.Both selective and non-selective β-blockers were reported to reduce mortality along with reducing markers of cardiac injury [1].

Limitations
Although there are very promising benefits of β-blocker usage in the management of sepsis and septic shock patients including a significant decrease in in-hospital mortality leading to better patient outcomes, the results also highlighted adverse events such as bradycardia, AV-nodal block, and hypotension [4,17].This raises a concern whether β-blockers are safe to use in hemodynamically unstable patients with sepsisinduced tachycardia.Therefore, further studies need to be done to assess the role of β-blockers in the blockers[Title/Abstract] AND mortality[Title/Abstract] AND septic shock[Title/Abstract]) AND English [Language] PubMed 29 ("Adrenergic beta-antagonists"[MeSH Terms] AND "Mortality"[MeSH Terms] AND "shock, septic"[MeSH Terms] AND "English"[Language]) AND ((y_10[Filter]) AND (fft[Filter]) AND (humans[Filter]

FIGURE 1 :
FIGURE 1: The PRISMA flowchart showing the article selection process.PRISMA: Preferred Reporting Items for the Systemic Review and Meta-Analysis

Figure 2
Figure2shows the pathophysiology of sepsis.

TABLE 3 : Quality appraisal using SANRA.
SANRA: Scale for the Assessment of Narrative Review

Table 6
shows the quality appraisal results using the Cochrane RoB 2 tool.

TABLE 6 : Quality appraisal using the Cochrane RoB 2 tool.
+: Low risk; ?: Some concerns; -: High risk; RoB: Risk-of-bias tool for randomized trials

Table 7
shows the summary of the finalized articles.